PURPOSE: We tested the hypothesis that polyphenol-rich extracts can reduce endoplasmic reticulum (ER) stress induced by a high-fat diet (HFD) in skeletal muscle of mice. METHODS: Mice were randomly assigned to four groups receiving during 20 weeks either a standard chow control (CTRL), or a HFD supplemented, or not, with pomegranate (HFD + P) or green tea (HFD + GT) extracts. After the nutritional intervention, mice were killed and gastrocnemius muscles were taken. Proteins and mRNA were measured by Western blot and RT-qPCR, respectively. RESULTS: Body weight gain and visceral fat were higher in HFD, HFD + P and HFD + GT than in CTRL. The markers of the unfolded protein response BiP, XBP1u, XBP1s and ATF4 were higher only in HFD. In HFD + P and HFD + GT, this increase was not observed except for CHOP, which was elevated in all HFD groups. HFD increased also markers of ubiquitin-proteasome pathway, autophagy and oxidative stress, which were kept low in HFD + P and HFD + GT groups. CONCLUSION: Our data provide evidence for a protective effect of pomegranate and green tea extracts against ER stress, oxidative stress and protein degradation induced by HFD in skeletal muscle. They give arguments for a usefulness of these natural nutritional compounds to fight against cellular dysfunctions related to fat excess.